ADCs can be used for the local delivery of drugs that can kill or inhibit the growth or division of target tissues or cells. The use of ADCs for the local delivery of cytotoxic or cytostatic agents to kill or inhibit tumour cells in the treatment of cancer has been described (see Anticancer Research (1999) 19:605-614; and Adv. Drug Delivery Rev. (1997) 26:151-172). Theoretically, the approach allows targeted delivery of a drug moiety to tumours, and intracellular accumulation therein, where systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells as well as the tumour cells sought to be eliminated (Lancet pp. (Mar. 15, 1986):603-05; and “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review,” (1985) in Monoclonal Antibodies '84: Biological And Clinical Applications, A. Pinchera et al. (ed.s), pp. 475-506). Maximal efficacy with minimal toxicity is therefore the ideal goal.
Drugs that have been used include daunomycin, doxorubicin, methotrexate, mitomycin, neocarzinostatin and vindesine. Toxins have also been used in antibody-toxin conjugates including bacterial toxins—such as diphtheria toxin; plant toxins—such as ricin; small molecule toxins—such as geldanamycin, macrocyclic depsipeptides and calicheamicin. The toxins may effect their cytotoxic and cytostatic effects by mechanisms including tubulin binding, DNA binding, or topoisomerase inhibition. Some cytotoxic drugs tend to be inactive or less active when conjugated to large antibodies or protein receptor ligands.
Considerable efforts have been invested in combining the desirable properties of monoclonal antibodies with the cell killing activity of cytotoxic drugs with the aim of reducing systemic toxicities and increase the therapeutic benefit for patients1. We have established ADCs using highly reliable traceless technologies based on disulfide bonds and thiazolidine heterocycles, for the chemical modification of antibody fragments bearing cysteines at the N- and C-terminus(2,3). In spite of their great potential and simplicity, ADCs are often not curative, and strategies to boost their activity are necessary.
Immunocytokines represent a novel class of biopharmaceuticals with a great potential for the therapy of cancers and chronic inflammation and autoimmune conditions, (depending on the cytokine used (e.g for cancer IL2, TNF; for inflammation IL10, IL2, IL12 and also TNF))4. Immunocytokines take advantage of antibody moieties as delivery vehicles for immune-modulating agents.
Cytokines such as interferons and interleukins show broad-based immunostimulatory effects, including generation of tumour-reactive lymphocytes. For example, interleukin-2 (IL-2) has been described for the treatment of metastatic renal cell carcinoma and melanoma. IL-2 activates cellular immunity and causes release of other immunostimulatory cytokines.
Systemic cytokine therapy is generally limited by rapid degradation and elimination of the cytokine, the inability to achieve optimal concentrations in the tumour, and dose-dependent toxicity, including life-threatening side effects such as vascular leak syndrome and orthostatic hypotension. As fusion proteins combining monoclonal antibodies with cytokines, immunocytokines were developed to improve upon the efficiency of monoclonal antibodies and cytokines alone or as combination therapy.
By targeting delivery of cytokines to the tumour, immunocytokines deliver biologically active concentrations of cytokines at lower and less toxic doses than are required by systemic cytokine therapy. In vivo administration of immunocytokines causes a greater anti-tumour effect than administration of a mixture of an equivalent dose of antibody and cytokine. Immunocytokines also appear to prolong cytokine biological activity relative to that of systemically administered cytokines.
We have developed a novel approach in which immunocytokines are combined with ADCs to obtain curative outcomes in the treatment of tumours and inflammatory conditions. We have also designed novel therapeutic drugs which combine immunocytokines and ADCs in a single molecule, which we refer to as an immunocytokine-drug conjugate (IDC).